Φλεγμονή και Καρκίνος

Παρακάτω μπορείτε να διαβάσετε ένα αρθρο του Εθνικού Ινστιτούτου των ΗΠΑ για τον Καρκίνο (NCI, http://www.cancer.gov/) σχετικά με τη σύνδεση της χρόνιας φλεγμονής και την γέννεση και πολλαπλασιασμό των καρκινικών κυττάρων. Στο σύνδεσμο μετά το άρθρο μπορείτε να διαβάσετε για την ανακάλυψη των ερευνητών του Πανεπιστημίου της Καλιφόρνια στο San Diego, αναφορικά με τη μοριακή σχέση της φλεγμονής και του καρκίνου.

Executive Summary of Inflammation and Cancer Think Tank

Inflammation is a response to acute tissue damage, whether resulting from physical injury, ischemic injury, infection, exposure to toxins, or other types of trauma. It can play a role in tumor suppression by stimulating an antitumor immune response, but more often it appears to stimulate tumor development. Epidemiologic and clinical research indicates an increased risk of certain cancers in the setting of chronic inflammation. For example, two inflammatory bowel diseases, ulcerative colitis and Crohn’s disease, predispose to cancers of the intestinal tract. Basic research, in turn, has shown that many of the processes involved in inflammation (e.g., leukocyte migration, dilatation of local vasculature with increased permeability and blood flow, angiogenesis), when found in association with tumors, are more likely to contribute to tumor growth, progression, and metastasis than to elicit an effective host anti-tumor response.
Interestingly, inflammation functions at all three stages of tumor development: initiation, progression and metastasis. Inflammation contributes to initiation by inducing the release of a variety of cytokines and chemokines that alert the vasculature to release inflammatory cells and factors into the tissue milieu, thereby causing oxidative damage, DNA mutations, and other changes in the microenvironment, making it more conducive to cell transformation, increased survival and proliferation.
Chronic inflammation appears to contribute to tumor progression by establishing a milieu conducive to development of different cancers. However the precise mechanism by which it does so remains to be determined. Infection is a common cause of inflammation, and evidence indicates that the presence of microbes can be a cofactor in the tumor promoting effects of inflammation.
Tumor cells produce various substances that attract inflammatory cells, which then secrete an array of soluble mediators. These further stimulate proliferation of the initiated cell, tissue disruption in the stroma, and tumor growth. Leukocyte infiltration, and particularly macrophages, can lead to enhanced angiogenesis, which is associated with a poor prognosis in some tissues.
The role of inflammation in metastasis is less well defined than its roles in cancer initiation and progression. The soluble mediators secreted by tumor-associated leukocytes promote cell motility, and induce angiogenesis, vascular dilation and extravasation of tumor cells. Particularly interesting is the recent finding that metastatic cells leave the tumor as microcolonies, containing lymphocytes and platelets as well as the tumor cell. Inflammation continues to play a role at metastatic sites by creating a cytokine milieu conducive to tumor growth.
Although there is a strong association between chronic inflammation and cancer, investigators have not yet uncovered all the molecules, pathways, and mechanisms involved, and numerous questions remain to be resolved about the mechanisms and targets of pro-inflammatory mediators of tumor development. These are articulated in the body of the report and the recommendations that follow. Furthermore, to understand the role of inflammation in tumor formation and progression, we also need to understand its role in maintaining homeostasis and responding to damage in normal tissue. An appreciation of the importance of inflammation has already led to clinical trials of anti-inflammatory drugs (e.g., COX-2 inhibitors) for cancer prophylaxis and treatment. The results obtained will provide clues to the dominant mechanisms at work, and will help in the design of a new generation of interventions.

Introduction
Inflammation involves a complex set of interactions between soluble mediators and immunocytes, triggered in response to tissue injuries that include trauma, infection, toxic agents and autoimmune responses. Such injuries trigger a cascade of cellular infiltrations and cytokine releases that result in local cellular proliferation and repair of tissue damaged. While sustained proliferation alone is insufficient to initiate cancer, a functional relationship between inflammation and cancer has been recognized for a long time. The current discussions centered on our current understanding of the role of inflammation in cancer initiation, progression and metastasis and highlighted areas in which there are major, unresolved questions.

Discussion Themes
I. Inflammation and Cancer Initiation
Although inflammation is a necessary response to clear viral infections, to repair tissue insults - either chemical exposure or injury- and suppress tumor initiation/progression, chronic inflammation is also clearly correlated with increased risk of developing cancer. Inflammation may become chronic either because an inflammatory stimulus persists or because of dysregulation in the control mechanisms that normally turn the process off. Many of the cells, cytokines and systems (e.g., leukocyte migration, dilatation of the local vasculature and angiogenesis) involved in inflammation are also found in a variety of tumors. Chronic inflammation caused by intestinal flora leading to the inflammatory bowel diseases, ulcerative colitis and Crohn’s disease, is clearly linked with a higher incidence of colon cancer. The use of mouse models has furthered our understanding of the contributing cellular and molecular factors in colon cancer. Similarly, dietary intake of proinflammatory carcinogens has been associated with prostate cancer. Chronic inflammation resulting from esophageal reflux gives rise to gastroesophageal reflux disease (GERD) and Barrett’s esophagus, also linked with a higher incidence of cancer. In the case of Barrett’s, chronic inflammation leads to the production of TNF". This, in turn, induces the nuclear translocation of $-catenin and transcriptional activation of proliferative signals.
The molecular basis for the increased risk is thought to be two-fold: 1) generation by inflammatory macrophages of reactive oxygen (ROS) and nitrogen (RNS) species leads to DNA damage in the surrounding epithelial cells and 2) enhanced proliferative signals mediated by cytokines released by inflammatory cells increase the number of cells at risk for mutations. In combination, DNA damage and proliferative signals create a circumstance conducive to the development of cancer. ROS and RNS can cause extensive damage to essential proteins (e.g., DNA repair enzymes), to DNA and to the mitochondria through a series or cascade of reactions. Among the many possible mutations that may result from oxidative DNA damage are the formation of single- and/or double-stranded breaks and the stimulation of recombination events. Free-radical damage can be caused by the pro-inflammatory prostaglandin enzyme, cyclooxygenase 2 (COX-2), which leads to the production of highly reactive peroxide intermediates at high levels in a local tissue environment. Drugs that selectively inhibit the COX-2 enzyme, including NSAIDs, are being studied to determine their impact on local tumor biology and development, and in clinical trials. Recent studies have suggested protective effects of COX-2 inhibitors in colorectal cancer and breast cancer. Several small studies of colorectal, non-small cell lung cancer, breast, cervical and esophageal tumors have shown that increased COX-2 levels are associated with poor clinical prognosis. Animal models for colorectal cancer show similar patterns of COX-2 expression and response to COX-2 inhibitors as human neoplasias.
Inflammation results in the recruitment of leukocytes secreting a variety of proliferative cytokines and angiogenic factors to the site of tissue insult. These cytokines, necessary for proper wound healing, stimulate epithelial proliferation, which if unchecked could lead to dysplasias and ultimately cancer. Paradoxically, cytokine deficiency (e.g., GM-CSF, IL-2 and IFN() can also lead to tumor development. Immune homeostasis consists of a succession of pro- and anti-inflammatory signals. Loss of the anti-inflammatory signals leads to chronic inflammation and proliferative signaling. The mechanisms involved in the interplay of microbes and defective immune homeostasis is an area that requires further delineation. Future steps will involve clinical studies to determine whether individuals have polymorphisms or genetic variations that affect specific cytokine pathways.
The discussion highlighted the duality of inflammation in controlling and promoting tumor development. While chronic inflammation can establish conditions conducive to tumor initiation and progression, compelling data also suggest that the presence of lymphocytic infiltrates in a variety of tumors is associated with a good clinical outcome. The major challenge in this area is to understand the balance between inflammatory tumor suppression and promotion and how to control it.

II. Inflammation and Cancer Progression
It is generally accepted that chronic inflammation – triggered by toxins, microbes or autoimmune reactions – plays a major role as a tumor promoter. However, the precise function of inflammation in tumor progression remains to be elucidated. Tumor cells produce various cytokines and chemokines that attract leukocytes, which in turn produce cytokines and chemokines that stimulate further tumor cell proliferation; the inflammatory tumor microenvironment is characterized by the presence of host leukocytes both in the stroma and around the tumor. A developing neoplasm can contain a diverse leukocyte population, including neutrophils, dendritic cells, macrophages, eosinophils, mast cells and lymphocytes. These inflammatory cells secrete an array of cytokines, interleukins, interferons and other soluble mediators and further induce secretion of cytokines by resident stromal cells.
Interestingly, both cytokines that promote and suppress proliferation of the tumor cells are produced. As in the case of cancer initiation, it is the imbalance between the effects of these two classes of activity that results in tumor promotion. For example, in the presence of GM-CSF and IL-4, monocytes differentiate into immature dendritic cells, which migrate into inflamed peripheral tissue, capture antigens and then migrate to lymph nodes to stimulate T lymphocyte activation. Deletion of GM-CSF from Polyoma T transgenic mice reduces cancer progression. This is correlated with reduced macrophage infiltrates, which play a major role in the transition from adenoma to carcinoma. GM-CSF vaccines that stimulate dendritic cell and T cell responses are being combined with anti-CTLA4 treatment in clinical trials to potentiate the anti-tumor response.
In contrast, IL-6 and CSF-1 secreted by tumor cells can skew monocyte differentiation towards the macrophage lineage. Although tumor associated macrophages can kill tumor cells when activated by IL-2, IL-12 or interferon, they also produce a host of compounds – angiogenic factors, growth factors, proteases and cytokines – that either contribute to cancer progression or blunt the anti-tumor response. Macrophages generate a variety of proteases, including cathepsin B, which contribute to tumor growth. Stromal fibroblasts and monocytes enhance this proteolysis. During tumor progression, the degradation of the matrix and stromal fibroblasts appears to be focal, suggesting that widespread degradation may not be necessary for tumor growth. In mammary cancer models, a variety of leukocytes are found at the tumor-stroma interface. A complex interaction between tumor, stroma and inflammatory cells results in the secretion of protease and matrix degradation and the entrapment and degradation of fibroblasts by the tumor.
Other studies have indicated that hypoxia signaling pathways are engaged very early in cancer development. Hypoxia stabilizes HIF-1" which in turn induces VEGF secretion by epithelial cells that stimulates microvascularization and angiogenesis.
The spatial relationship between inflammatory cells and tumors is now being investigated by imaging of a range of live human tumor and associated cells. Examination of the interaction reveals that although T cells will home to the tumor, they stay on the periphery and do not enter. Real-time images of mammary tumors in mice show that the tumor regions are metabolically active, compared with surrounding stroma and fat cells. These regions also have a much greater inflammatory response; associated immune cells, particulary T cells, are very active and mobile. In mammary cancer models, imaging reveals that tumor associated macrophages preferentially line up along the lumenal side of the tumor-associated vessels. Macrophages in this region are relatively static, whereas those at the stromal interface are very active and motile, suggesting differential behavior within the tumor. The functional significance of this remains to be determined.
Although the role of inflammatory cells and soluble mediators in tumor progression is now well documented, the details of the cellular and molecular interplay between stroma and tumor progression remain to be elucidated.

III. Inflammation and Metastasis
Unlike tumor progression, where the role of inflammation in promoting cancer cell proliferation and stromal/matrix degradation is reasonably well understood, the role of inflammation in metastasis is less well defined, although appears to be important. The cytokines and chemokines secreted by tumor associated macrophages and leukocytes promote cell motility and induce angiogenesis and the growth of tumor-associated vessels, providing an egress route for metastatic tumor cells. The leukocytes also promote vessel dilation and extravasation of tumor cells. Particularly intriguing is the observation that metastatic cells leave the tumor as microcolonies, containing lymphocytes and platelets, the latter allowing attachment to distal organ sites. Tumors that are unable to form such microcolonies are not malignant.
At the distal, metastatic sites, evidence suggests that inflammation continues to play a role in the establishment of metastases. At the sites of prostate cancer metastases in the bone, inflammation triggers the secretion of TGF-β by osteoclasts. TGF-β in turn induces the cancer cells to secrete PDGF which further stimulates the osteoclasts, leading to bone degradation and stimulation of cancer cell growth. PDGFR on tumor-associated endothelial cells increases their levels of bcl-2 and bcl-xl, rendering them resistant to apoptosis and chemotherapy. Similarly, in brain metastases of melanoma, astrocytic infiltrates upregulate MDR (multiple drug resistance) in the tumor cells, making them more resistant to chemotherapy.

Next Steps and Important Questions
Despite the evidence for the role of inflammation in cancer intiation, progression and metastases, other evidence suggests that cancer proceeds through inflammation-dependent and independent stages. These stages need to be defined and characterized.
To better understand the critical role of inflammation in initiating and modulating tumor behavior, host-pathogen interactions need to be defined at a molecular level, the phenotypes of hematopoeitic cells (leukocytes, monocytes, platelets, etc) involved in wound repair and tumor initiation need to be characterized and the roles of endocrinological mediators on inflammation need to be examined.
To better understand the role of inflammation in tumor progression, tumor stage should be correlated with intensity and repertoire of hematopoietic infiltrates and with the levels of cytokines and proteases present; biomarkers for pre-malignant and malignant lesions need to be identified and validated.
To better understand the role of inflammation in metastasis, better pre-clinical models need to be developed, the molecular relationship between primary and metastatic tumor cells needs to be resolved, the nature of the inflammatory responses that influence primary versus metastatic tumor need to be determined, and the role of the hematopoietic network in tumor extravasation and migration needs to be elucidated.
Real-time imaging models need to be refined and extended to allow better definition of the relationship between inflammatory and tumor cells that influence the cancer initiation, progression and metastasis process.
Tumor immunotherapy approaches should include targeted intervention of inflammation-mediated growth, pairing molecular information of inflammatory infiltrates with that of specific tumors. Therapy should be specifically directed to both the organ microenvironment and the tumor.

Specific Recommendations for the NCI:
-Continue to support basic research aimed at characterizing the role of inflammation at all stages of cancer and specifically at determining the role of hematopoeitic cells in both metastasis and normal development.
-Encourage collaborative studies between basic and clinical investigators.

-Support studies that characterize inflammatory cells in the tumor microenvironment and correlate these with clinical outcomes and prognosis
-Consider mechanisms to stimulate multi-agency, multi-institutional and transdisciplinary collaborations to more rigorously define critical interactions that occur between tumor cells and their inflammatory microenvironment.
-Sponsor a series of workshops and/or interactive fora on inflammation and cancer that interface experts from different disciplines (i.e., toxicologists, cellular and tumor immunologists, systems biologists, cancer biologists).
-Develop and standardize reagents and protocols for analysis of archived tissues. -Establish a uniform database of existing reagents and well-defined and catalogued tumor types that are or are not associated with inflammation.
-Establish and make available conditional tissue- or cell-specific pre-clinical models to study the biology of inflammation-dependent cancers and to stimulate novel prevention, diagnostic and therapeutic strategies.
-Consider mechanisms to provide investigators with

1. access to imaging tools for in vitro and in vivo analysis to characterize immunocyte/tumor interactions.
2. more sophisticated and cheaper imaging modalities, perhaps by encouraging development in the private sector through the SBIR mechanism
3. training in the use and application of imaging techniques

"Molecular Link Between Inflammation And Cancer Discovered"

http://www.sciencedaily.com/releases/2007/01/070125122719.htm